Question

What would you do next?

Increase the risperidone (Risperdal) back to 4 mg/d as everything was working well before the dose reduction

Switch his current atypical antipsychotic to one that is more sedating and dose at night

Continue escalating the clonazepam (Klonopin) anxiolytic for better effect

Add an approved sleep-inducing agent in addition to his current regimen

Case outcome: second interim follow-up visits through 12 months (continued)

Instead of escalating clonazepam (Klonopin), the patient is placed on the BZRA approved sleeping agent, zolpidem (Ambien) 10 mg at bedtime, with no effect

It is doubled, off-label, with no effect

Clonazepam (Klonopin) is increased to 3 mg/d without effect

Eventually, he agrees to switch from risperidone (Risperdal) to another atypical with a more sedating, sleep-inducing profile

• – He is titrated on to quetiapine (Seroquel) up to 400 mg/d, the minimal effective dose for psychosis

• – Zolpidem (Ambien) 20 mg at bedtime is discontinued as it was ineffective

• – Clonazepam (Klonopin) is reduced gradually back to 1 mg/d as it was ineffective at higher doses

• – He begins sleeping better

Question

Why did the BZRA zolpidem (Ambien) not work, but the atypical quetiapine (Seroquel) did help his insomnia?

Some drugs will not work in certain individual patients

The moderate-dose BZ (clonazepam [Klonopin]) was already facilitating GABA-A receptor activity, likely desensitizing GABA-A receptors in the CNS sleep centers so that the added BZRA agent, zolpidem, was less likely to be effective as it works mechanistically in a similar fashion and faced pre-existing GABA-A receptor desensitization

Quetiapine (Seroquel) is an effective atypical antipsychotic with strong anthistamine activity. This H1 receptor antagonism-induced fatigue and somnolence through a non-GABAergic mechanism and hence was more effective

Quetiapine (Seroquel) has properties where noradrenergic alpha-1 receptors are antagonized, inducing sleepiness as a side effect

Quetiapine (Seroquel) has serotonin (5-HT2A) receptor antagonism and this may promote deeper, more efficient sleep architecture on EEG

Attending physician’s mental notes: interim visits through 18 months

The patient now has symptoms more consistent with anxiety and a hypochondriacal thought process. He seems to be getting nocebo (essentially placebo-induced adverse effects) effects

He may have had hallucinations telling him to “freeze” but he denies this upon questioning

The freezing spells have stopped

He seems genuinely disapproving of another trial of atypical antipsychotics

It is possible that the multifactorial activity of the atypical antipsychotics at different receptor sites is causing him random, ill-defined side effects

He is sleeping well, which is a relief

Case outcome: interim follow-up visits through 18 months

The patient does well and sleep improves, but now starts to gain weight on quetiapine (Seroquel) and also begins to have many somatic symptoms and “freezing spells”

• – These spells happen once or twice a week where he may be sitting on the couch and either becomes catatonic or panicky and “freezes” where he feels he cannot move

Both clonazepam (Klonopin) and quetiapine (Seroquel) are increased to 3 mg/d and 600 mg/d, respectively, as this is a presumed recurrence of catatonic psychosis

• – He does not worsen, but he does not respond

• – Becomes overly sedated especially in the morning

Quetiapine (Seroquel) is tapered off as it is ineffective now and oversedating

• – Next fails a subtherapeutic trial of ziprasidone (Geodon) due to many odd somatic complaints, possibly nocebo effects

• – Then fails a subtherapeutic trial of aripiprazole (Abilify) due to many odd somatic complaints

• – He recollects that haloperidol (Haldol) was helpful in the past and asks if it, or a similar medicine, can be taken now